Following the Hedgehog

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Cellular Signaling Pathway Could Lead Scientists to a Cure for Cancer

Just a decade removed from her days as a doctoral student at the University of Illinois at Urbana-Champaign, Xiaoyan Zheng, Ph.D., assistant professor of anatomy and regenerative medicine at GW’s School of Medicine and Health Sciences (SMHS), boasts a depth and experience with her subject that extends well beyond her years. Her research, funded by a grant from the National Institutes of Health, focuses on an oddly named cellular signaling pathway, the Hedgehog pathway, that transmits critical information to embryonic cells in order to direct their proper development and regeneration.

Xiaoyan Zheng, Ph.D.

Hedgehogs are peculiar enough creatures in nature, spiky hairballs that curl up when threatened. So why name such a crucial pathway after the odd little animal? The explanation, as well as the roots of the research, extends back into the 1980s when scientists were studying gene mutations in Drosophila, or fruit flies. Rather than the typical pattern of alternating bald and hairlike strips in the larvae, scientists found that Hedgehog pathways in the mutant larvae tended to be short and stubby with dense lawns of denticles — small pointy projections — resembling the namesake mammal. From her second-floor lab in Ross Hall, Zheng is studying the regulation of cell-to-cell interaction along this pathway; her research may one day lead to a cure for cancer.

The Hedgehog signaling pathway is one of the key regulators of animal development and is present in all animals with bilateral symmetry, that is, those that have a front and back, as well as an “up” side and a “down” side. Different parts of the embryo have different concentrations of Hedgehog signaling proteins. Malfunctions of this pathway have been associated with several diseases, including cancer.

“So, I study the mechanism of how the Hedgehog proteins can have this effect,” explains Zheng. “The cells sense the Hedgehog with a receptor, and that receptor interacts with other ‘downstream’ proteins, telling the cells what to do. “We already know that abnormal Hedgehog pathway activity causes cancer,” she continues. “What we don’t know is how to effectively interrupt this pathway to stop the development of cancer.” The flip side is that if you stop the Hedgehog signaling completely, it may affect the cell’s other normal functions.

From December 2005 until December 2011, Zheng was a postdoctoral fellow with Philip A. Beachy, Ph.D., first at Johns Hopkins and then at Stanford University. Beachy is a pioneer in the field, and his lab studies the mechanism underlying Hedgehog signal transduction.

“My primary research is in identifying target genes regulated by the Hedgehog signal and thus [understanding] the molecular mechanisms employed by the Hedgehog signaling pathway in regulating cell-to-cell interactions,” Zheng says. If she can identify more of the proteins regulated by the Hedgehog signal, she may have more new targets for affecting the signal. “Through my research, I hope to identify new genes that are controlled by the Hedgehog signal, and these genes are potential drug targets for curing cancer.”


Zheng is also interested in developing novel reagents and experimental approaches combined with cutting-edge imaging technologies to study the biochemical and cell biological principles governing a critical, yet poorly understood, step of Hedgehog signal transduction: trafficking of Hedgehog pathway proteins in different subcellular domains. “We use photoconversion assays to study ciliary trafficking of Hedgehog pathway proteins,” explains Zheng. By using a fluorescent protein tag, Zheng and her team are able to study the “ciliary entry and exit of the Hedgehog signaling proteins in individual cells.” Both studies will go a long way toward helping researchers better understand pathway dysfunction and could lead to therapeutic solutions for modulating pathway activity, either to stimulate regeneration or to block malignant growth.

Zheng arrived at SMHS in January 2013, and with the help of her team — two postdoctoral assistants, a lab technician, and three undergraduate assistants — got the lab up and running. Since then the team’s research progress has steadily picked up speed, and now Zheng is preparing an application for a new National Institutes of Health R01 grant. “We’re still in the beginning stage of the research, but [we’ve been] gradually making progress during the past two years. I believe our progress in the next two years will be more dramatic,” she says confidently.

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